Arylsulfonamide ccr3 antagonists

ABSTRACT

Provided herein are arylsulfonamides that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disorder, disease, or condition.

Priority is claimed herein to U.S. Provisional Application No.61/314,971, entitled “Arylsulfonamide CCR3 Antagonists,” filed Mar. 17,2010. The above-referenced application is incorporated by referenceherein in its entirety.

FIELD

Provided herein are arylsulfonamides that are useful for modulating CCR3activity, and pharmaceutical compositions thereof. Also provided hereinare methods of their use for treating, preventing, or ameliorating oneor more symptoms of a CCR3-mediated disorder, disease, or condition.

BACKGROUND

CC chemokine receptor 3 (CCR3) is a seven-transmembrane Gprotein-coupled receptor, which binds to a variety of C—C chemokines,including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4(CCL13), and RANTES (CCL5). CCR3 is known to be a major chemokinereceptor expressed on allergic inflammatory cells, includingeosinophils, basophils, mast cells, and T helper 2-type CD4⁺ cells(Combadiere et al., J. Biol. Chem. 1995, 270, 16491-16494; Post et al.,J. Immunol. 1995, 155, 5299-5305). Eosinophils have been implicated inthe pathogenesis of a number of allergic diseases, such as bronchialasthma (Durham and Kay, Clin. Allergy 1985, 15, 411-418; Kroegel et al,J. Allergy Clin. Immunol. 1994, 93, 725-734), allergic rhinitis (Durham,Clin. Exp. Allergy 1998, 28 Suppl. 2, 11-16), atopic dermatitis (Leung,J. Allergy Clin. Immunol. 1999, 104, S99-108), and eosinophilicgastroenteritis (Bischoff et al., Am. J. Gastro. 1999, 94, 3521-3529).It has been demonstrated that activated eosinophils release major basicprotein (MBP), which blocks inhibitory M2 muscarinic receptors (M2Rs) onnerves, increasing acetylcholine release, and potentiating vagallymediated bronchoconstriction (Evans et al., J. Clin. Invest. 1997, 100,2254-2262).

Numerous reports indicate that CCR3 plays important roles in allergicconditions. For example, it has been reported that, in both atopic andnonatopic asthma patients, there are increases in both mRNA and proteinlevels of CCR3 and its ligands, eotaxin, eotaxin-2, RANTES, and MCP-4(Ying et al., J. Immunol. 1999, 99, 6321-6329). It has also beendemonstrated that CCR3 gene deletion impairs eosinophil recruitment inan acute model of experimental asthma (Humbles et al., Proc. Natl. Acad.Sci. USA 2002, 99, 1479-1484; Ma et al., J. Clin. Invest. 2002, 109,621-628; Pope et al., J. Immunol. 2005, 175, 5341-5350; Fulkerson etal., Proc. Natl. Acad. Sci. USA 2006, 103, 16418-16423). Furthermore,studies have shown that CCR3 antagonists, such as anti-CCR3 monoclonalantibodies, block binding of CCR3-ligands to either CCR3 transfectantsor eosinophils, thus blocking chemotaxis of eosinophils induced by C—Cchemokines, such as eotaxin, RANTES, or MCP-3 (Heath et al., J. Clin.Invest. 1997, 99, 178-184; Grimaldi et al., J. Leukocyte Biol. 1999, 65,846-853; Justice et al., Am. J. Physiol. 2003, 284, L168-L178).Therefore, CCR3 antagonists are potentially useful for the treatment ofinflammatory diseases, such as allergic rhinitis and allergic asthma. Inaddition, CCR3 antagonists are also potentially useful blockinginfection of CCR3 expressing cells by some microorganisms, such as HIV,as CCR3 is known to be an entry co-receptor for some microorganisms.

SUMMARY OF THE DISCLOSURE

Provided herein are arylsulfonamide compounds of Formulae I and II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently (a) hydrogen, halo,cyano, nitro, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;(c) deuterium; or (d) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁷ is (a) hydrogen, halo, cyano, nitro, oxo, or guanidine; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

X is O or S;

Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a);

R⁸ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; or

Y and R⁸ together with the N atom to which they are attached formheteroaryl or heterocyclyl;

Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a);

m is an integer from 0 to 3;

R⁹ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4; and

each R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; or each pair of R^(1b) and R^(1c)together with the N atom to which they are attached independently formheteroaryl or heterocyclyl, with the proviso that R^(1e) is not t-butylor benzyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moregroups, each independently selected from (a) cyano, halo, and nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q;

wherein each Q is independently selected from the group consisting of(a) deuterium; (b) cyano, halo, and nitro; (c) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (d) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g);

wherein each R^(e), R^(f), R^(g), and R^(h) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f)and R^(g) together with the N atom to which they are attached formheterocyclyl.

In one embodiment, the compound is of Formula I, with the proviso thatif Y and R⁸ together with the N atom to which they are attached formheteroaryl, the heteroaryl comprises at least one additional O, S, or Natom.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I or II,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; in combination with one or more pharmaceuticallyacceptable carriers.

Further provided herein is a method for modulating CCR3 activity,comprising contacting a CCR3 with a therapeutically effective amount ofa compound disclosed herein, e.g., a compound of Formula I or II,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

Additionally provided herein is a method for treating, preventing, orameliorating one or more symptoms of a CCR3-mediated disorder, disease,or condition in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I or II, an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, or a mixture of two ormore tautomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. In the eventthat there is a plurality of definitions for a term used herein, thosein this section prevail unless stated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substituted asdescribed herein. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀, or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms). For example, C₁₋₆ alkyl refers to alinear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s). The alkenyl maybe optionally substituted as described herein. The term “alkenyl” alsoembraces radicals having “cis” and “trans” configurations, oralternatively, “Z” and “E” configurations, as appreciated by those ofordinary skill in the art. As used herein, the term “alkenyl”encompasses both linear and branched alkenyl, unless otherwisespecified. For example, C₂₋₆ alkenyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Incertain embodiments, the alkenyl is a linear monovalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of alkenyl groups include, but are not limited to,ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s). The alkynyl maybe optionally substituted as described herein. The term “alkynyl” alsoencompasses both linear and branched alkynyl, unless otherwisespecified. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH) and propargyl(—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted as described herein. In oneembodiment, cycloalkyl groups may be saturated, and/or bridged, and/ornon-bridged, and/or fused bicyclic groups. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10(C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent multicyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀),from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, andterphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, whereone of the rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthyl,indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certainembodiments, aryl may be optionally substituted as described herein.

The term “aralkyl” or “aryl-alkyl” refers to a monovalent alkyl groupsubstituted with aryl. In certain embodiments, the alkyl and arylmoieties are optionally substituted as described herein.

The term “alkoxy” refers to the group “—OR” where R is alkyl orcycloalkyl. Alkoxy groups include, by way of example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, and 1,2-dimethylbutoxy.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupand/or multicyclic aromatic group that contain at least one aromaticring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring.Heteroaryl groups are bonded to the rest of the molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms, provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system and/or multicyclic ring system thatcontains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, or N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of the moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay include a fused or bridged ring system, and in which the nitrogen orsulfur atoms may be optionally oxidized, the nitrogen atoms may beoptionally quaternized, and some rings may be partially or fullysaturated, or aromatic. The heterocyclyl may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heterocyclic radicals include,but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, O-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted as described herein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group, suchas an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, orheterocyclyl group, may be substituted with one or more substituentsindependently selected from, e.g., (a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q; and (b) halo,cyano (—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heteroaryl or heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ. As used herein, all groups that can be substituted are “optionallysubstituted,” unless otherwise specified. As used herein, the term“optionally substituted” is also intended to include the substitution ofa hydrogen with a deuterium atom.

In one embodiment, each Q is independently selected from the groupconsisting of (a) deuterium; (b) cyano, halo, and nitro; (c) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (d) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof one enantiomer and about 5% or less of the other enantiomer based onthe total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “CCR3” refers to CC chemokine receptor 3 or a variant thereof,which is capable of mediating a cellular response to a variety ofchemokines, including, but not limited to, eotaxin (CCL11), eotaxin-3(CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). CCR3 variantsinclude proteins substantially homologous to a native CCR3, i.e.,proteins having one or more naturally or non-naturally occurring aminoacid deletions, insertions or substitutions (e.g., CCR3 derivatives,homologs and fragments), as compared to the amino acid sequence of anative CCR3. The amino acid sequence of a CCR3 variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native CCR3.

The term “CCR3 antagonist” refers to a compound that, e.g., partially ortotally blocks, decreases, prevents, inhibits, or downregulates CCR3activity. The term “CCR3 antagonist” also refers to a compound thatbinds to, delays the activation of, inactivates, or desensitizes a CCR3receptor. A CCR3 antagonist may act by interfering with the interactionof a CCR3 receptor and its chemokine ligand, including, but not limitedto, eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13),and/or RANTES (CCL5).

The terms “CCR3-mediated disorder or disease” and “a condition, disorderor disease mediated by CCR3” refer to a condition, disorder, or diseasecharacterized by inappropriate, e.g., less than or greater than normal,CCR3 activity. Inappropriate CCR3 functional activity might arise as theresult of CCR3 expression in cells which normally do not express CCR3,increased CCR3 expression or degree of intracellular activation, leadingto, e.g., inflammatory and immune-related disorders or diseases; ordecreased CCR3 expression. A CCR3-mediated condition, disorder ordisease may be completely or partially mediated by inappropriate CCR3activity. In particular, a CCR3-mediated condition, disorder or diseaseis one in which modulation of a CCR3 receptor results in some effect onthe underlying condition or disorder, e.g., a CCR3 antagonist or agonistresults in some improvement in at least some of patients being treated.

Compounds

Provided herein are arylsulfonamides which are useful for modulatingCCR³ activity. Also provided herein are pharmaceutical compositionswhich comprise the compounds and methods of use of the compounds andcompositions for the treatment of a CCR³-mediated disorder, disease, orcondition.

In one embodiment, provided herein are arylsulfonamide compounds ofFormulae I and II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently (a) hydrogen,deuterium, halo, cyano, nitro, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁷ is (a) hydrogen, halo, cyano, nitro, oxo, or guanidine; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), C(NR^(1a))NR^(1b)R^(1c), OR^(1a), OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

X is O or S;

Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a);

R⁸ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; or

Y and R⁸ together with the N atom to which they are attached formheteroaryl or heterocyclyl;

Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a);

m is an integer from 0 to 3;

R⁹ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4; and

each R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; or each pair of R^(1b) and R^(1c)together with the N atom to which they are attached independently formheteroaryl or heterocyclyl, with the proviso that R^(1e) is not t-butylor benzyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moregroups, each independently selected from (a) cyano, halo, and nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q;

wherein each Q is independently selected from the group consisting of(a) deuterium; (b) cyano, halo, and nitro; (c) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (d) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g);

wherein each R^(e), R^(f), R^(g), and R^(h) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f)and R^(g) together with the N atom to which they are attached formheterocyclyl.

In another embodiment, provided herein are arylsulfonamide compounds ofFormulae Ia and IIa:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;

Wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), R^(1e), X, Y, Z, m, n, and p are as defined herein;

R^(d) is deuterium; and

q is an integer from 0 to 3.

The groups, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), R^(1e), X, Y, Z, m, n, p and q in Formulae I, II, Ia and IIa arefurther defined in the embodiments described herein. All combinations ofthe embodiments provided herein for such groups are within the scope ofthis disclosure.

In certain embodiments, R¹ is hydrogen, deuterium, halo, cyano, nitro,or guanidine. In certain embodiments, R¹ is hydrogen. In certainembodiments, R¹ is deuterium. In certain embodiments, R¹ is halo. Incertain embodiments, R¹ is fluoro or chloro. In certain embodiments, R¹is C₁₋₆ alkyl, optionally substituted as described herein. In certainembodiments, R¹ is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R¹ is methyl, ethyl, propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, ort-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R¹ is methyl. In certainembodiments, R¹ is C₁₋₆ alkoxy, optionally substituted as describedherein. In certain embodiments, R¹ is C₁₋₆ alkoxy, optionallysubstituted with one, two, or three halo. In certain embodiments, R¹ isC₁₋₆ alkylthio, optionally substituted as described herein. In certainembodiments, R¹ is C₁₋₆ alkylthio, optionally substituted with one, two,or three halo. In certain embodiments, R¹ is C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted as described herein. In certain embodiments,R¹ is —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R² is hydrogen, deuterium, halo, cyano, nitro,or guanidine. In certain embodiments, R² is hydrogen. In certainembodiments, R² is halo. In certain embodiments, R² is fluoro or chloro.In certain embodiments, R² is C₁₋₆ alkyl, optionally substituted asdescribed herein. In certain embodiments, R² is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R² ismethyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R²is methyl. In certain embodiments, R² is C₁₋₆ alkoxy, optionallysubstituted as described herein. In certain embodiments, R² is C₁₋₆alkoxy, optionally substituted with one, two, or three halo. In certainembodiments, R² is C₁₋₆ alkylthio, optionally substituted as describedherein. In certain embodiments, R² is C₁₋₆ alkylthio, optionallysubstituted with one, two, or three halo. In certain embodiments, R² isC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted as describedherein. In certain embodiments, R² is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c); C(NR^(1a))NR^(1b)R^(1c); —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), NR^(1a)C(O)R^(1d), NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R³ is hydrogen, deuterium, halo, cyano, nitro,or guanidine. In certain embodiments, R³ is hydrogen. In certainembodiments, R³ is halo. In certain embodiments, R³ is fluoro or chloro.In certain embodiments, R³ is C₁₋₆ alkyl, optionally substituted asdescribed herein. In certain embodiments, R³ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R³ ismethyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R³is methyl. In certain embodiments, R³ is C₁₋₆ alkoxy, optionallysubstituted as described herein. In certain embodiments, R³ is C₁₋₆alkoxy, optionally substituted with one, two, or three halo. In certainembodiments, R³ is C₁₋₆ alkylthio, optionally substituted as describedherein. In certain embodiments, R³ is C₁₋₆ alkylthio, optionallysubstituted with one, two, or three halo. In certain embodiments, R³ isC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted as describedherein. In certain embodiments, R³ is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a); R^(1b);R^(1c); and R^(1d) are each as defined herein.

In certain embodiments, R⁴ is hydrogen, deuterium, halo, cyano, nitro,or guanidine. In certain embodiments, R⁴ is hydrogen. In certainembodiments, R⁴ is halo. In certain embodiments, R⁴ is fluoro or chloro.In certain embodiments, R⁴ is C₁₋₆ alkyl, optionally substituted asdescribed herein. In certain embodiments, R⁴ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁴ ismethyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R⁴is methyl. In certain embodiments, R⁴ is C₁₋₆ alkoxy, optionallysubstituted as described herein. In certain embodiments, R⁴ is C₁₋₆alkoxy, optionally substituted with one, two, or three halo. In certainembodiments, R⁴ is C₁₋₆ alkylthio, optionally substituted as describedherein. In certain embodiments, R⁴ is C₁₋₆ alkylthio, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁴ isC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted as describedherein. In certain embodiments, R⁴ is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c); —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)S(O)₂R^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R⁵ is hydrogen, deuterium, halo, cyano, nitro,or guanidine. In certain embodiments, R⁵ is hydrogen. In certainembodiments, R⁵ is halo. In certain embodiments, R⁵ is fluoro or chloro.In certain embodiments, R⁵ is C₁₋₆ alkyl, optionally substituted asdescribed herein. In certain embodiments, R⁵ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁵ ismethyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R⁵is methyl. In certain embodiments, R⁵ is C₁₋₆ alkoxy, optionallysubstituted as described herein. In certain embodiments, R⁵ is C₁₋₆alkoxy, optionally substituted with one, two, or three halo. In certainembodiments, R⁵ is C₁₋₆ alkylthio, optionally substituted as describedherein. In certain embodiments, R⁵ is C₁₋₆ alkylthio, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁵ isC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted as describedherein. In certain embodiments, R⁵ is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, two of R¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆alkyl, optionally substituted as described herein. In certainembodiments, two of R¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆ alkyl, whichis optionally substituted as described herein, and the remaining threeare hydrogen. In certain embodiments, two of R¹, R², R³, R⁴, and R⁵ arechloro or methyl. In certain embodiments, two of R¹, R², R³, R⁴, and R⁵are chloro or methyl, and the remaining three are hydrogen. In certainembodiments, R¹, R³, and R⁵ are hydrogen, and R² and R⁴ are halo or C₁₋₆alkyl, optionally substituted as described herein. In certainembodiments, R¹, R³, and R⁵ are hydrogen or deuterium, and R² and R⁴ arehalo or C₁₋₆ alkyl, optionally substituted as described herein. Incertain embodiments, R¹, R³, and R⁵ are hydrogen, and R² and R⁴ arechloro or methyl. In certain embodiments, R¹, R³, and R⁵ are hydrogen,and R² and R⁴ are chloro. In certain embodiments, R¹, R³, and R⁵ arehydrogen, and R² and R⁴ are methyl. In certain embodiments, R², R³, andR⁵ are hydrogen, and R¹ and R⁴ are halo or C₁₋₆ alkyl, optionallysubstituted as described herein. In certain embodiments, R², R³, and R⁵are hydrogen, and R¹ and R⁴ are chloro or methyl. In certainembodiments, R², R³, and R⁵ are hydrogen, and R¹ and R⁴ are chloro. Incertain embodiments, R², R³, and R⁵ are hydrogen, and R¹ and R⁴ aremethyl.

In certain embodiments, R⁶ is hydrogen, halo, cyano, nitro, orguanidine. In certain embodiments, R⁶ is hydrogen. In certainembodiments, R⁶ is halo. In certain embodiments, R⁶ is fluoro or chloro.In certain embodiments, R⁶ is cyano. In certain embodiments, R⁶ isnitro. In certain embodiments, R⁶ is C₁₋₆ alkyl, optionally substitutedas described herein. In certain embodiments, R⁶ is C₁₋₆ alkyl,optionally substituted with one, two, or three halo. In certainembodiments, R⁶ is methyl, ethyl, propyl (e.g., n-propyl and isopropyl),butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g.,n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is C₁₋₆alkoxy, optionally substituted as described herein. In certainembodiments, R⁶ is C₁₋₆ alkoxy, optionally substituted with one, two, orthree halo. In certain embodiments, R⁶ is C₁₋₆ alkylthio, optionallysubstituted as described herein. In certain embodiments, R⁶ is C₁₋₆alkylthio, optionally substituted with one, two, or three halo. Incertain embodiments, R⁶ is C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each optionallysubstituted as described herein. In certain embodiments, R⁶ is—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R⁷ is hydrogen, halo, cyano, nitro, oxo, orguanidine. In certain embodiments, R⁷ is hydrogen. In certainembodiments, R⁷ is halo. In certain embodiments, R⁷ is fluoro or chloro.In certain embodiments, R⁷ is cyano. In certain embodiments, R⁷ isnitro. In certain embodiments, R⁷ is oxo. In certain embodiments, R⁷ isC₁₋₆ alkyl, optionally substituted as described herein. In certainembodiments, R⁷ is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁷ is methyl, ethyl, propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, ort-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R⁷ is methyl. In certainembodiments, R⁷ is C₁₋₆ alkoxy, optionally substituted as describedherein. In certain embodiments, R⁷ is C₁₋₆ alkoxy, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁷ isC₁₋₆ alkylthio, optionally substituted as described herein. In certainembodiments, R⁷ is C₁₋₆ alkylthio, optionally substituted with one, two,or three halo. In certain embodiments, R⁷ is C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted as described herein. In certain embodiments,R⁷ is —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isC₁₋₆ alkyl, optionally substituted as described herein. In certainembodiments, R⁸ is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁸ is methyl, ethyl, propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, ort-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R⁸ is methyl. In certainembodiments, R⁸ is C₃₋₇ cycloalkyl.

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isC₁₋₆ alkyl, optionally substituted as described herein. In certainembodiments, R⁹ is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁹ is methyl, ethyl, propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, ort-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R⁹ is methyl. In certainembodiments, R⁹ is C₃₋₇ cycloalkyl.

In certain embodiments, X is O. In certain embodiments, X is S.

In certain embodiments, Y is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, Y is —C(O)—C₁₋₆ alkyl. In certainembodiments, Y is —C(O)—C₂₋₆ alkenyl. In certain embodiments, Y is—C(O)—C₃₋₇ cycloalkyl. In certain embodiments, Y is —C(O)—C₆₋₁₄ aryl. Incertain embodiments, Y is —C(O)—C₇₋₁₅ aralkyl. In certain embodiments, Yis —C(S)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, Y is —C(S)—C₁₋₆ alkyl. In certain embodiments, Y is—C(S)—C₂₋₆ alkenyl. In certain embodiments, Y is —C(S)—C₃₋₇ cycloalkyl.In certain embodiments, Y is —C(S)—C₆₋₁₄ aryl. In certain embodiments, Yis —C(S)—C₇₋₁₅ aralkyl. In certain embodiments, Y is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, Y is —C(O)NH—C₁₋₆ alkyl. In certain embodiments, Y is—C(O)NH—C₁₋₆ alkyl, wherein the C₁₋₆ alkyl group is substituted withone, two, or three halo. In certain embodiments, Y is —C(O)NH—C₁₋₆alkyl, wherein the C₁₋₆ alkyl group is substituted with heterocyclyl. Inone embodiment, Y is —C(O)NH—C₁₋₆ alkyl, wherein the C₁₋₆ alkyl group issubstituted with heterocyclyl, and wherein if the C₁₋₆ alkyl group isethyl, the heterocyclyl is not morpholino. In certain embodiments, Y is—C(O)NH—C₂₋₆ alkenyl. In certain embodiments, Y is —C(O)NH—C₃₋₇cycloalkyl. In certain embodiments, Y is —C(O)NH—C₆₋₁₄ aryl. In certainembodiments, Y is —C(O)NH—C₇₋₁₅ aralkyl. In certain embodiments, Y is—C(S)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, Y is —C(S)NH—C₁₋₆ alkyl. In certainembodiments, Y is —C(S)NH—C₂₋₆ alkenyl. In certain embodiments, Y is—C(S)NH—C₃₋₇ cycloalkyl. In certain embodiments, Y is —C(S)NH—C₆₋₁₄aryl. In certain embodiments, Y is —C(S)NH—C₇₋₁₅ aralkyl. In certainembodiments, Y is —S(O)R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, Y is —S(O)—C₁₋₆ alkyl. In certain embodiments, Y is—S(O)—C₂₋₆ alkenyl. In certain embodiments, Y is —S(O)—C₃₋₇ cycloalkyl.In certain embodiments, Y is —S(O)—C₆₋₁₄ aryl. In certain embodiments, Yis —S(O)—C₇₋₁₅ aralkyl. In certain embodiments, Y is —S(O)₂R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, Y is—S(O)₂—C₁₋₆ alkyl. In certain embodiments, Y is —S(O)₂—C₂₋₆ alkenyl. Incertain embodiments, Y is —S(O)₂—C₃₋₇ cycloalkyl. In certainembodiments, Y is —S(O)₂—C₆₋₁₄ aryl. In certain embodiments, Y is—S(O)₂—C₇₋₁₅ aralkyl.

In certain embodiments, Y and R⁸ together with the N atom to which theyare attached form heteroaryl or heterocyclyl. In one embodiment, Y andR⁸ together with the N atom to which they are attached form heteroaryl.In one embodiment, Y and R⁸ together with the N atom to which they areattached form heteroaryl, wherein heteroaryl comprises at least oneadditional O, S, or N atom. In one embodiment, Y and R⁸ together withthe N atom to which they are attached form triazolyl, optionallysubstituted as described herein. In one embodiment, Y and R⁸ togetherwith the N atom to which they are attached form heterocyclyl.

In certain embodiments, Z is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, Z is —C(O)—C₁₋₆ alkyl. In certainembodiments, Z is —C(O)—C₂₋₆ alkenyl. In certain embodiments, Z is—C(O)—C₃₋₇ cycloalkyl. In certain embodiments, Z is —C(O)—C₆₋₁₄ aryl. Incertain embodiments, Z is —C(O)—C₇₋₁₅ aralkyl. In certain embodiments, Zis —C(S)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, Z is —C(S)—C₁₋₆ alkyl. In certain embodiments, Z is—C(S)—C₂₋₆ alkenyl. In certain embodiments, Z is —C(S)—C₃₋₇ cycloalkyl.In certain embodiments, Z is —C(S)—C₆₋₁₄ aryl. In certain embodiments, Zis —C(S)—C₇₋₁₅ aralkyl. In certain embodiments, Z is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, Z is —C(O)NH—C₁₋₆ alkyl. In certain embodiments, Z is—C(O)NH—C₂₋₆ alkenyl. In certain embodiments, Z is —C(O)NH—C₃₋₇cycloalkyl. In certain embodiments, Z is —C(O)NH—C₆₋₁₄ aryl. In certainembodiments, Z is —C(O)NH—C₇₋₁₅ aralkyl. In certain embodiments, Z is—C(S)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, Z is —C(S)NH—C₁₋₆ alkyl. In certainembodiments, Z is —C(S)NH—C₂₋₆ alkenyl. In certain embodiments, Z is—C(S)NH—C₃₋₇ cycloalkyl. In certain embodiments, Z is —C(S)NH—C₆₋₁₄aryl. In certain embodiments, Z is —C(S)NH—C₇₋₁₅ aralkyl. In certainembodiments, Z is —S(O)R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, Z is —S(O)—C₁₋₆ alkyl. In certain embodiments, Z is—S(O)—C₂₋₆ alkenyl. In certain embodiments, Z is —S(O)—C₃₋₇ cycloalkyl.In certain embodiments, Z is —S(O)—C₆₋₁₄ aryl. In certain embodiments, Zis —S(O)—C₇₋₁₅ aralkyl. In certain embodiments, Z is —S(O)₂R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, Z is—S(O)₂—C₁₋₆ alkyl. In certain embodiments, Z is —S(O)₂—C₂₋₆ alkenyl. Incertain embodiments, Z is —S(O)₂—C₃₋₇ cycloalkyl. In certainembodiments, Z is —S(O)₂—C₆₋₁₄ aryl. In certain embodiments, Z is—S(O)₂—C₇₋₁₅ aralkyl.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2. In certain embodiments, m is 3.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3.

In certain embodiments, m is 1 and n is 1. In certain embodiments, m is1 and n is 2.

In certain embodiments, p is 1. In certain embodiments, p is 2. Incertain embodiments, p is 3. In certain embodiments, p is 4.

In certain embodiments, q is 0. In certain embodiments, q is 1. Incertain embodiments, q is 2. In certain embodiments, q is 3.

In certain embodiments, R^(1a) is hydrogen. In certain embodiments,R^(1a) is C₁₋₆ alkyl, optionally substituted as described herein. Incertain embodiments, R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl orheteroaryl. In certain embodiments, R^(1a) is methyl, ethyl, propyl(e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl,or t-butyl), or pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1a) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1a) is C₂₋₆ alkenyl, optionally substitutedas described herein. In certain embodiments, R^(1a) is C₂₋₆ alkynyl,optionally substituted as described herein. In certain embodiments,R^(1a) is C₃₋₇ cycloalkyl, optionally substituted as described herein.In certain embodiments, R^(1a) is C₃₋₇ cycloalkyl, optionallysubstituted with one or two C₁₋₆ alkyl. In certain embodiments, R^(1a)is C₃₋₇ cycloalkyl, optionally substituted with two methyl groups. Incertain embodiments, R^(1a) is cyclobutyl, cyclopentyl, cyclohexyl, ordimethylbicyclo-[2.2.1]heptyl (e.g., 7,7-dimethylbicyclo[2.2.1]-heptyl).In certain embodiments, R^(1a) is cyclobutyl, cyclopentyl, cyclohexyl,or (1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl. In certain embodiments,R^(1a) is C₆₋₁₄ aryl, optionally substituted as described herein. Incertain embodiments, R^(1a) is C₆₋₁₄ aryl, optionally substituted withone or more halo or C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, or three halo. In certain embodiments, R^(1a)is C₆₋₁₄ aryl, optionally substituted with fluoro, chloro, methyl,trifluoromethyl, or ethyl. In certain embodiments, R^(1a) is phenyl,fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl),chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl),methylphenyl (e.g., 2-methylphenyl, 3-methylphenyl, or 4-methylphenyl),trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl). In certainembodiments, R^(1a) is phenyl, 3-fluorophenyl, 3-methylphenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, or4-ethylphenyl. In certain embodiments, R^(1a) is heteroaryl, optionallysubstituted as described herein. In certain embodiments, R^(1a) isheterocyclyl.

In certain embodiments, R^(1b) is hydrogen. In certain embodiments,R^(1b) is C₁₋₆ alkyl, optionally substituted as described herein. Incertain embodiments, R^(1b) is C₁₋₆ alkyl, optionally substituted withone or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl orheteroaryl. In certain embodiments, R^(1b) is C₂₋₆ alkenyl, optionallysubstituted as described herein. In certain embodiments, R^(1b) is C₂₋₆alkynyl, optionally substituted as described herein. In certainembodiments, R^(1b) is C₃₋₇ cycloalkyl, optionally substituted asdescribed herein. In certain embodiments, R^(1b) is C₆₋₁₄ aryl,optionally substituted as described herein. In certain embodiments,R^(1b) is heteroaryl, optionally substituted as described herein. Incertain embodiments, R^(1b) is heterocyclyl, optionally substituted asdescribed herein.

In certain embodiments, R^(1c) is hydrogen. In certain embodiments,R^(1c) is C₁₋₆ alkyl, optionally substituted as described herein. Incertain embodiments, R^(1c) is C₁₋₆ alkyl, optionally substituted withone or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl orheteroaryl. In certain embodiments, R^(1c) is methyl, ethyl, propyl(e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl,or t-butyl), or pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1c) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1c) is C₂₋₆ alkenyl, optionally substitutedas described herein. In certain embodiments, R^(1c) is C₂₋₆ alkynyl,optionally substituted as described herein. In certain embodiments,R^(1c) is C₃₋₇ cycloalkyl, optionally substituted as described herein.In certain embodiments, R^(1c) is C₃₋₇ cycloalkyl, optionallysubstituted with one or two C₁₋₆ alkyl. In certain embodiments, R^(1c)is C₃₋₇ cycloalkyl, optionally substituted with two methyl groups. Incertain embodiments, R^(1c) is cyclobutyl, cyclopentyl, cyclohexyl, ordimethylbicyclo-[2.2.1]heptyl (e.g., 7,7-dimethylbicyclo[2.2.1]-heptyl).In certain embodiments, R^(1c) is cyclobutyl, cyclopentyl, cyclohexyl,or (1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl. In certain embodiments,R^(1c) is C₆₋₁₄ aryl, optionally substituted as described herein. Incertain embodiments, R^(1c) is C₆₋₁₄ aryl, optionally substituted withone or more halo or C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, or three halo. In certain embodiments, R^(1c)is C₆₋₁₄ aryl, optionally substituted with fluoro, chloro, methyl,trifluoromethyl, or ethyl. In certain embodiments, R^(1c) is phenyl,fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl),chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl),methylphenyl (e.g., 2-methylphenyl, 3-methylphenyl, or 4-methylphenyl),trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl). In certainembodiments, R^(1c) is phenyl, 3-fluorophenyl, 3-methylphenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, or4-ethylphenyl. In certain embodiments, R^(1c) is heteroaryl, optionallysubstituted as described herein. In certain embodiments, R^(1c) isheterocyclyl.

In certain embodiments, R^(1b) and R^(1c) together with the N atom towhich they are attached independently form heteroaryl, optionallysubstituted as described herein. In certain embodiments, R^(1b) andR^(1c) together with the N atom to which they are attached independentlyform heterocyclyl, optionally substituted as described herein.

In certain embodiments, R^(1d) is hydrogen. In certain embodiments,R^(1d) is C₁₋₆ alkyl, optionally substituted as described herein. Incertain embodiments, R^(1d) is C₂₋₆ alkenyl, optionally substituted asdescribed herein. In certain embodiments, R^(1d) is C₂₋₆ alkynyl,optionally substituted as described herein. In certain embodiments,R^(1d) is C₃₋₇ cycloalkyl, optionally substituted as described herein.In certain embodiments, R^(1d) is C₆₋₁₄ aryl, optionally substituted asdescribed herein. In certain embodiments, R^(1d) is heteroaryl,optionally substituted as described herein. In certain embodiments,R^(1d) is heterocyclyl, optionally substituted as described herein.

In certain embodiments, R^(1e) is hydrogen. In certain embodiments,R^(1e) is C₁₋₆ alkyl, optionally substituted as described herein, withthe proviso that R^(1e) is not t-butyl. In certain embodiments, R^(1e)is C₁₋₆ alkyl, optionally substituted with one or more halo, C₁₋₆alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl. In certainembodiments, R^(1e) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), n-butyl, 2-butyl, isobutyl, or pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments,R^(1e) is methyl, ethyl, isopropyl, isobutyl, 1,1-dimethylpropyl, or2,2-dimethylpropyl. In certain embodiments, R^(1e) is C₂₋₆ alkenyl,optionally substituted as described herein. In certain embodiments,R^(1e) is C₂₋₆ alkynyl, optionally substituted as described herein. Incertain embodiments, R^(1e) is C₃₋₇ cycloalkyl, optionally substitutedas described herein. In certain embodiments, R^(1e) is C₃₋₇ cycloalkyl,optionally substituted with one or two C₁₋₆ alkyl. In certainembodiments, R^(1e) is C₃₋₇ cycloalkyl, optionally substituted with twomethyl groups. In certain embodiments, R^(1e) is cyclobutyl,cyclopentyl, cyclohexyl, or dimethylbicyclo-[2.2.1]heptyl (e.g.,7,7-dimethylbicyclo[2.2.1]-heptyl). In certain embodiments, R^(1e) iscyclobutyl, cyclopentyl, cyclohexyl, or(1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl. In certain embodiments,R^(1e) is C₆₋₁₄ aryl, optionally substituted as described herein. Incertain embodiments, R^(1e) is C₆₋₁₄ aryl, optionally substituted withone or more halo or C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, or three halo. In certain embodiments, R^(1e)is C₆₋₁₄ aryl, optionally substituted with fluoro, chloro, methyl,trifluoromethyl, or ethyl. In certain embodiments, R^(1e) is phenyl,fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl),chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl),methylphenyl (e.g., 2-methylphenyl, 3-methylphenyl, or 4-methylphenyl),trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl). In certainembodiments, R^(1e) is phenyl, 3-fluorophenyl, 3-methylphenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, or4-ethylphenyl. In certain embodiments, R^(1e) is heteroaryl, optionallysubstituted as described herein. In certain embodiments, R^(1e) isheterocyclyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁸ is hydrogen or C₁₋₆ alkyl;

X is O or S;

m is 0, 1, or 2;

n is 1 or 2;

p is 1, 2, 3, or 4; and

Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that R^(1e) is not t-butyl or benzyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁸ is hydrogen or C₁₋₆ alkyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a) and R^(1c) are each independently (a) C₁₋₆ alkyl, optionallysubstituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio,heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionally substitutedwith one or more halo; (c) C₃₋₇ cycloalkyl, optionally substituted withone or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄ aryl, optionallysubstituted with one or more halo, C₁₋₆ alkyl, where the alkyl isfurther optionally substituted with one, two, or three halo or C₁₋₆alkoxy, where the alkoxy is further optionally substituted with one,two, or three halo; (e) heteroaryl, optionally substituted with one ortwo C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with one ormore halo, C₁₋₆ alkyl, where the alkyl is further optionally substitutedwith one, two, or three halo, or C₁₋₆ alkoxy, where the alkoxy isfurther optionally substituted with one, two, or three halo; and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁸ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y is —C(O)R^(1a) or —C(S)R^(1a); wherein

R^(1a) is (a) C₁₋₆ alkyl, optionally substituted with one or more halo;(b) C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionallysubstituted with one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁸ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y is —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein

R^(1b) is hydrogen; and

R^(1c) is (a) C₁₋₆ alkyl, optionally substituted with one or more haloor C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionally substitutedwith one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁸ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1; and

Y is —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein

R^(1b) is hydrogen; and

R^(1c) is C₁₋₆ alkyl optionally substituted with (a) one or more halo;or (b) heterocyclyl; and

R^(1b) is hydrogen or methyl.

In one embodiment, in Formula I,

R¹ is hydrogen;

R² is chloro;

R³ is hydrogen;

R⁴ is chloro;

R⁵ is hydrogen;

R⁶ is cyano;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4;

Y is —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein

R^(1b) is hydrogen;

R^(1c) is C₁₋₆ alkyl optionally substituted with (a) one or more halo;or (b) heterocyclyl; and

R^(1b) is hydrogen or methyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁸ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y is —S(O)₂R^(1a); wherein

R^(1a) is (a) C₁₋₆ alkyl; (b) C₆₋₁₄ aryl, optionally substituted withone or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or (c) heteroaryl,optionally substituted with one or two C₁₋₆ alkyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y and R⁸ together with the N atom to which they are attached formheteroaryl, wherein the heteroaryl comprises at least one additional O,S, or N atom, optionally substituted with one or two C₁₋₆ alkyl groups.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y and R⁸ together with the N atom to which they are attached form a 5membered heteroaryl, wherein the heteroaryl comprises at least oneadditional O, S, or N atom, optionally substituted with one or two C₁₋₆alkyl groups.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y and R⁸ together with the N atom to which they are attached formtriazolyl, optionally substituted with one or two methyl groups.

In another embodiment, in Formula I,

R¹ is hydrogen;

R² is chloro or methyl;

R³ is hydrogen;

R⁴ is chloro or methyl;

R⁵ is hydrogen;

R⁶ is cyano;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Y and R⁸ are as defined elsewhere herein.

In one embodiment, in Formula Ia,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl;

R⁶ is cyano or nitro;

R⁸ is hydrogen;

R^(d) is deuterium;

X is O or S;

m is 0, 1, or 2;

n is 1 or 2;

p is 1, 2, 3, or 4;

q is 3; and

Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In another embodiment, in Formula Ia,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl;

R⁶ is cyano;

R⁸ is hydrogen;

R^(d) is deuterium;

X is O or S;

m is 1;

n is 1;

p is 4;

q is 3; and

Y is —C(O)R^(1a), c(s)R^(1a), C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In another embodiment, in Formula Ia,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl;

R⁶ is cyano;

R⁸ is hydrogen;

R^(d) is deuterium;

X is O or S;

m is 1;

n is 1;

p is 4;

q is 3; and

Y is —C(O)NR^(1b)R^(1c); wherein

R^(1c) is (a) C₁₋₆ alkyl, optionally substituted with one or more halo,C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆alkenyl, optionally substituted with one or more halo; (c) C₃₋₇cycloalkyl, optionally substituted with one or more halo, or one or twoC₁₋₆ alkyl; (d) C₆₋₁₄ aryl, optionally substituted with one or morehalo, C₁₋₆ alkyl, where the alkyl is further optionally substituted withone, two, or three halo or C₁₋₆ alkoxy, where the alkoxy is furtheroptionally substituted with one, two, or three halo; (e) heteroaryl,optionally substituted with one or two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyloptionally substituted with one or more halo, C₁₋₆ alkyl, where thealkyl is further optionally substituted with one, two, or three halo, orC₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; and

R^(1b) is hydrogen.

In another embodiment, in Formula Ia,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano;

R⁸ is hydrogen;

R^(d) is deuterium;

X is O or S;

m is 1;

n is 1;

p is 4;

q is 3; and

Y is —C(O)NR^(1b)R^(1c); wherein

R^(1c) is (a) C₁₋₆ alkyl substituted with heterocyclyl; or (b) C₂₋₆alkenyl; and

R^(1b) is hydrogen.

In one embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁹ is hydrogen or C₁₋₆ alkyl;

X is O or S;

m is 0, 1, or 2;

n is 1 or 2;

p is 1, 2, 3, or 4; and

Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that R^(1e) is not t-butyl or benzyl.

In one embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁹ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Z is —C(O)R^(1a) or —C(S)R^(1a); wherein

R^(1a) is (a) C₁₋₆ alkyl, optionally substituted with one or more halo;(b) C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionallysubstituted with one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy.

In one embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁹ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Z is —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein

R^(1b) is hydrogen; and

R^(1c) is (a) C₁₋₆ alkyl, optionally substituted with one or more haloor C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionally substitutedwith one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In one embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen;

R⁹ is hydrogen or methyl;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Z is —S(O)₂R^(1a); wherein

R^(1a) is (a) C₁₋₆ alkyl; (b) C₆₋₁₄ aryl, optionally substituted withone or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or (c) heteroaryl,optionally substituted with one or two C₁₋₆ alkyl.

In another embodiment, in Formula II,

R¹ is hydrogen;

R² is chloro or methyl;

R³ is hydrogen;

R⁴ is chloro or methyl;

R⁵ is hydrogen;

R⁶ is cyano;

R⁷ is hydrogen;

X is O or S;

m is 1;

n is 1;

p is 1, 2, 3, or 4; and

Z and R⁹ are as defined elsewhere herein.

In one embodiment, in Formula IIa,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl;

R⁶ is cyano or nitro;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁹ is hydrogen or C₁₋₆ alkyl;

R^(d) is deuterium;

X is O or S;

m is 0, 1, or 2;

n is 1 or 2;

p is 1, 2, 3, or 4; and

q is 3; and

Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), C(S)NR^(1b)R^(1c),C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein

R^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and

R^(1b) is hydrogen or methyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, and mixtures of two or more tautomers thereofand pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

In one embodiment, the compound provided here is a hydrochloride salt.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I orII, and is readily convertible into the parent compound in vivo.Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent compound. They may, for instance,be bioavailable by oral administration whereas the parent compound isnot. The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

Compounds provided herein may be prepared, isolated, or obtained by anymethod known to one of skill in the art. For an example, a compound ofFormula I can be prepared as shown in Scheme 1, where P¹ is hydrogen oran amino protecting group, e.g., Boc, Cbz, or Fmoc; and R^(L) is aleaving group, e.g., chloro, bromo, iodo, imidazole, or a carboxylate.

Compound A reacts with compound B via a nucleophilic aromaticsubstitution reaction to form compound C with release of hydrochloride.The nitro group of the compound C was reduced to an amino group with areducing reagent, e.g., sodium hydrosulfite or tin (II) chloride, toform analine D, which is subsequently converted into sulfonyl chloride Evia the Sandmeyer reaction. Compound E is then coupled with amine F,wherein amino protecting group P¹ is optional in some embodiments. Theremoval of protecting group P¹ from compound G leads to compound H,which is reacted with Y-R^(L) to form a compound of Formula I.

An alternative route to a compound of Formula I is shown in Scheme 2.

In a method similar to that described above and shown in Scheme 1, acompound of Formula II can be prepared as shown in Scheme 3, where P¹ ishydrogen or an amino protecting group, e.g., Boc, Cbz, or Fmoc; andR^(L) is a leaving group, e.g., chloro, bromo, iodo, imidazole, or acarboxylate.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I or II, as an activeingredient, including an enantiomer, a mixture of enantiomers, a mixtureof two or more diastereomers, a tautomer, or a mixture of two or moretautomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; in combination with a pharmaceuticallyacceptable vehicle, carrier, diluent, or excipient, or a mixturethereof.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I or II, can be formulated in various dosageforms for oral, parenteral, and topical administration. Thepharmaceutical compositions can also be formulated as modified releasedosage forms, including delayed-, extended-, prolonged-, sustained-,pulsatile-, controlled-, accelerated-, fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I or II, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; and one or more pharmaceutically acceptable excipientsor carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I or II, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; and one or more pharmaceutically acceptable excipientsor carriers.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of alower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking Examples ofsuitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionassociated with CCR3 in a subject, which comprises administering to thesubject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I or II, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In another embodiments, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionresponsive to the modulation of CCR3 activity in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula I or II, includingan enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method of treating, preventing,or ameliorating one or more symptoms of a disorder, disease, orcondition mediated by a CCR3 receptor in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula I or II, includingan enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula I orII, including an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisorder, disease, or condition in a subject, comprising administeringto a subject, a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I or II, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of a mast cell-relateddisorder, disease, or condition in a subject, comprising administeringto a subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I or II, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula I or II, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

The disorders, diseases, or conditions treatable with a compoundprovided herein, e.g., a compound of Formula I or II, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the disorder, disease, or condition is selectedfrom the group consisting of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease, Churg-Strauss syndrome, sinusitis, basophilicleukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema,COPD (chronic obstructive pulmonary disorder), arthritis, rheumatoidarthritis, psoriatic arthritis, and osteoarthritis.

In certain embodiments, the disorder, disease, or condition is asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, chronicobstructive plumonary disease, or allergic conjunctivitis.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofasthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever,sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis,multiple sclerosis, atherosclerosis, transplant rejection, inflammatorybowel disease, cancer, or other conditions, disorders or diseasesassociated with a CCR3 receptor, an appropriate dosage level generallyis ranging from about 0.001 to 100 mg per kg subject body weight per day(mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day,or from about 1 to about 20 mg/kg per day, which can be administered insingle or multiple doses. Within this range, the dosage can be rangingfrom about 0.005 to about 0.05, from about 0.05 to about 0.5, from about0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, orfrom about 1 to about 50 mg/kg per day. In certain embodiments, thedosage level is ranging from about 0.001 to about 100 mg/kg per day. Incertain embodiments, the dosage level is ranging from about 0.01 toabout 75 mg/kg per day. In certain embodiments, the dosage level isranging from about 0.1 to about 50 mg/kg per day. In certainembodiments, the dosage level is ranging from about 0.5 to about 25mg/kg per day. In certain embodiments, the dosage level is ranging fromabout 1 to about 20 mg/kg per day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Also provided herein are methods of modulating CCR3 activity, comprisingcontacting a CCR3 receptor with a compound provided herein, e.g., acompound of Formula I or II, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the CCR3 receptor is expressed by a cell.

The compounds provided herein, e.g., a compound of Formula I or II,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, can also be combined or used in combination with otheragents useful in the treatment, prevention, or amelioration of one ormore symptoms of the disorders, diseases, or conditions for which thecompounds provided herein are useful, including asthma, allergicrhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemiclupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted above.

In certain embodiments, the compounds provided herein can be combinedwith one or more steroidal drugs known in the art, including, but notlimited to the group including, aldosterone, beclometasone,betamethasone, deoxycorticosterone acetate, fludrocortisone,hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone,dexamethasone, and triamcinolone.

In certain embodiments, the compounds provided herein can be combinedwith one or more antibacterial agents known in the art, including, butnot limited to the group including amikacin, amoxicillin, ampicillin,arsphenamine, azithromycin, aztreonam, azlocillin, bacitracin,carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin,cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime,cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin,imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide,quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin,sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antifungal agents known in the art, including, but notlimited to the group including amorolfine, amphotericin B,anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,ciclopirox, clotrimazole, econazole, fenticonazole, filipin,fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole,posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine,terconazole, tioconazole, and voriconazole.

In certain embodiments, the compounds provided herein can be combinedwith one or more anticoagulants known in the art, including, but notlimited to the group including acenocoumarol, argatroban, bivalirudin,lepirudin, fondaparinux, heparin, phenindione, warfarin, andximelagatran.

In certain embodiments, the compounds provided herein can be combinedwith one or more thrombolytics known in the art, including, but notlimited to the group including anistreplase, reteplase, t-PA (alteplaseactivase), streptokinase, tenecteplase, and urokinase.

In certain embodiments, the compounds provided herein can be combinedwith one or more non-steroidal anti-inflammatory agents known in theart, including, but not limited to, aceclofenac, acemetacin, amoxiprin,aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antiplatelet agents known in the art, including, butnot limited to, abciximab, cilostazol, clopidogrel, dipyridamole,ticlopidine, and tirofibin.

The compounds provided herein can also be administered in combinationwith other classes of compounds, including, but not limited to, (1)alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompounds provided herein, e.g., a compound of Formula I or II,including a single enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof. When a compound provided herein is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compoundprovided herein can be utilized, but is not required. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, including a single enantiomer or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); HPLC (high pressure liquid chromatography);THF (tetrahydrofuran); CDCl₃ (deuterated chloroform); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EtOAc(ethyl acetate); MeOH (methanol); and BOC (t-butyloxycarbonyl).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Preparation ofN-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-fluorobenzenesulfonamide(25)

Commercially available 4-chloro-3-benzonitrile was dissolved in 4 partsTHF. One part water was added with sodium hydrosulfide (3 eq.) andstirred overnight at 45° C. TLC (25% EtOAc in hexanes) confirmedcompletion of the reaction. THF was evaporated in vacuo and the productprecipitated. The white solid was collected via vacuum filtration,washed with water and dried in a vacuum oven with gentle heating (97.0%yield).

The aniline product was ground in a mortar and pestle and dissolved in amixture of 11 parts HCl and 4 parts acetic acid. In a separate vessel,50 parts acetic acid was stirred with SO₂ gas until saturation(confirmed by weight). The HCl:acetic acid:aniline mixture was placed ina dry ice/ethanol bath at 10° C. Sodium nitrite (1.1 eq.) was dissolvedin a minimal amount of water and added dropwise to the HCl:aceticacid:aniline mixture without allowing the temperature to rise aboveabout −5° C. The resulting mixture was stirred 45 minutes to form thediazonium ion. Copper (I) chloride (0.1 eq.) and copper (II) chloride(0.25 eq.) were added to the SO₂/acetic acid solution and stirred 30minutes and cooled in an ice bath to 10° C. The diazonium mixture wasadded in portions to the copper (I)/copper (II) chloride suspension,maintaining a temperature of 30° C. or lower. Once fully combined, themixture was stirred until gas evolution ceased, forming a dark greensolution. The mixture was then poured into 200 parts ice water slowlywith stirring until the ice melted. The resulting white precipitate wascollected by vacuum filitration and washed with water (72.9% yield).

2-Chloro-5-cyanobenzene-1-sulfonyl chloride (8.00 g) was dissolved in100 ml THF and N-BOC-4-aminopiperidine (5.79 g) was added. Slowly 6equiv. of K₂CO₃ was added and the mixture stirred 1 hour at roomtemperature. 3,5-dichlorophenol (11.06 g) and 18-Crown-6 (4.66 g) wereadded and the reaction stirred 4 days at reflux (75° C.). The mixturewas cooled and vacuum filtered, the filtrate concentrated in vacuo,redissolved in methylene chloride, partitioned with water and theaqueous layer extracted three times with methlyene chloride. Thecombined organic layers were washed with saturated sodium bicarbonate,water, brine and dried over MgSO₄. The filtrate was concentrated invacuo, triturated with methylene chloride/diisopropyl ether and vacuumfiltered to afford a yellow powder. The powder was recrystallized inMeOH to afford the product as a white powder (14.50 g, 87.3%).

The BOC-protected amine (11.00 g) was suspended in methylene chloride(40.0 mL) and 11.0 ml of trifluoroacetic acid was added. The startingmaterial was consumed after 22 hours of stirring (confirmed by HPLC).The mixture was condensed in vacuo and the resulting oil brought to pH 7by addition of 3N NaOH (36.0 mL). The white suspension was filtered invacuo, and the solid recrystallized in MeOH to afford a white powder(6.51 g, 73.0%).

The amine starting material,3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile,(100 mg) was dissolved in 3.0 mL of methylene chloride, and triethylamine (0.042 mL, 1.3 eq.) followed by 3-fluorobenzesulfonyl chloride (58mg, 1.3 eq.) was added. The starting material was consumed after 3.5hours of stirring, as confirmed by TLC (50% EtOAc/hexanes). Purificationby normal phase silica gel chromatography (14%, 35% EtOAc/Hexanes)provided the desired product, which was triturated with diisopropylether and vacuum filtered to yield a white powder (61 mg, 44.5%). ¹H NMR(500 MHz, CDCl₃) δ: 8.24 (d, J=2 Hz, 1H), 7.78 (dd, J1=9 Hz, J2=2 Hz,1H), 7.53 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 6.99 (m, 3H), 4.93 (t,J=7 Hz, 1H), 3.26 (m, 1H), 2.46 (m, 2H), 1.89 (m, 2H), 1.65 (m, 2H). MS(ESI+ ion, m/z): 585.

Example 2 Preparation of1-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(3-fluorophenyl)urea(4)

3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrilewas prepared following the procedure of Example 1. The final product wasprepared by the addition of triethyl amine (0.42 mL) followed by3-fluorophenyl isocyanate to a solution of3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile(102 mg) in methylene chloride (4.0 mL). After stirring for 3 hours, thestarting material was consumed, as confirmed by TLC (50% EtOAc/hexanes).4 mL of hexanes was added and the product collected by vacuum filtrationand washed with 1N HCl. The desired product was obtained as a whitepowder (99 mg, 73.3%). ¹H NMR (500 MHz, DMSO-d₆) δ: 8.61 (s, 1H), 8.28(d, J=2 Hz, 1H), 8.13 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.55 (t, J=2 Hz, 2H),7.42 (m, 1H), 7.37 (d, J=2 Hz, 2H), 7.34 (d, J=9 Hz, 1H), 7.22 (m, 1H),6.99 (m, 1H), 6.68 (m, 1H), 6.33 (d, J=8 Hz, 1H), 3.61 (m, 3H), 2.96 (m,2H), 1.88 (m, 2H), 1.40 (m, 2H). MS (ESI+ ion, m/z): 564.

Example 3N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)benzamide(1)

Compound 1 was prepared according to the methods described herein. ¹HNMR (500 MHz, CDCl₃) δ: 8.32 (d, J=1 Hz, 1H), 7.79 (dd, J1=9 Hz, J2=2Hz, 1H), 7.74 (d, J=8 Hz, 2H), 7.52 (m, 1H), 7.44 (m, 2H), 7.30 (s, 1H),7.04 (d, J=9 Hz, 1H), 7.00 (s, 2H), 5.98 (J=7 Hz, 1H), 4.12 (m, 1H),3.96 (m, 2H), 2.92 (m, 2H), 2.14 (m, 2H), 1.62 (m, 2H). MS (ESI+ ion,m/z): 531.

Example 4N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)methanesulfonamide(3)

Compound 3 was prepared according to the methods described herein. ¹HNMR (500 MHz, CDCl₃) δ: 8.30 (d, J=2 Hz, 1H), 7.79 (dd, J1=9 Hz, J2=2Hz, 1H), 7.30 (t, J=2 Hz, 1H), 7.03 (d, J=9 Hz, 1H), 6.98 (d, J=2 Hz,2H), 4.19 (m, 1H), 3.85 (m, 2H), 3.47 (m, 1H), 2.99 (s, 3H), 2.91 (m,1H), 2.09 (m, 2H), 1.63 (m, 2H). MS (ESI+ ion, m/z): 505.

Example 5N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)acetamide(5)

Compound 5 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.36 (d, J=2 Hz,2H), 7.32 (d, J=9 Hz, 1H), 3.67 (m, 1H), 3.61 (m, 2H), 2.91 (m, 2H),1.77 (m, 5H), 1.36 (m, 2H). MS (ESI+ ion, m/z): 469.

Example 6N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)isobutyramide(6)

Compound 6 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.25 (s, 1H), 8.10 (d, J=9 Hz, 1H), 7.68 (s,1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.30 (d, J=9 Hz, 1H), 3.64 (m, 3H),2.90 (m, 2H), 1.76 (m, 2H), 1.36 (m, 2H), 0.96 (d, J=7 Hz, 6H). MS (ESI+ion, m/z): 497.

Example 7N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide(7)

Compound 7 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.76 (d, J=8 Hz, 1H), 8.28 (d, J=2 Hz, 1H),8.12 (dd, J1=2 Hz, J2=9 Hz, 1H), 7.56 (t, J=2 Hz, 1H), 7.38 (d, J=2 Hz,2H), 7.33 (d, J=9 Hz, 1H), 3.93 (m, 1H), 3.69 (m, 2H), 2.96 (m, 2H),2.74 (s, 3H), 1.91 (m, 2H), 1.51 (m, 2H). MS (ESI+ ion, m/z): 553.

Example 84-chloro-N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)butanamide(8)

Compound 8 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=2 Hz, J2=9 Hz,1H), 7.87 (d, J=8 Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.36 (d, J=2 Hz, 2H),7.32 (d, J=9 Hz, 1H), 3.70 (m, 1H), 3.61 (m, 4H), 2.92 (m, 2H), 2.20 (m,2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.37 (m, 2H).

Example 9

N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)cyclobutanecarboxamide(9)

Compound 9 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.11 (dd, J1=9 Hz, J2=2Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.37 (d, J=2 Hz,2H), 7.31 (d, J=9 Hz, 1H), 3.68 (m, 1H), 3.62 (m, 2H), 2.91 (m, 3H),2.08 (m, 2H), 1.97 (m, 2H), 1.86 (m, 1H), 1.76 (m, 3H), 1.35 (m, 2H).

Example 10N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-4-methylbenzamide(10)

Compound 10 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J=2 Hz, 1H), 8.22 (d, J=8 Hz, 1H),8.12 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.73 (d, J=8 Hz, 2H), 7.55 (t, J=2 Hz,1H), 7.39 (d, J=2 Hz, 2H), 7.32 (d, J=9 Hz, 1H), 7.25 (d, J=8 Hz, 2H),3.94 (m, 1H), 3.73 (m, 2H), 2.93 (m, 2H), 2.34 (s, 3H), 1.87 (m, 2H),1.56 (m, 2H).

Example 11N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-fluorobenzamide(11)

Compound 11 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.40 (d, J=8 Hz, 1H), 8.28 (d, J=2 Hz, 1H),8.12 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.68 (d, J=7 Hz, 1H), 7.55 (t, J=2 Hz,1H), 7.52 (m, 1H), 7.39 (d, J=2 Hz, 2H), 7.37 (m, 1H), 7.33 (d, J=9 Hz,1H), 3.95 (m, 1H), 3.73 (m, 2H), 2.94 (m, 2H), 1.88 (m, 2H), 1.56 (m,2H).

Example 121-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-isopropylurea(12)

Compound 12 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.12 (dd, J1=2 Hz, J2=9Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.36 (d, J=2 Hz, 2H), 7.33 (d, J=9 Hz,1H), 5.75 (d, J=8 Hz, 1H), 5.55 (d, J=8 Hz, 1H), 3.63 (m, 1H), 3.58 (m,2H), 3.50 (m, 1H), 2.91 (m, 2H), 1.79 (m, 2H), 1.30 (m, 2H), 0.99 (d,J=6 Hz, 6H).

Example 131-allyl-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)urea(13)

Compound 13 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.36 (d, J=2 Hz, 2H), 7.33 (d, J=9 Hz,1H), 5.95 (d, J=8 Hz, 1H), 5.84 (m, 1H), 5.07 (m, 1H), 5.00 (m, 1H),3.61 (m, 3H), 3.52 (m, 2H), 2.91 (m, 2H), 1.81 (m, 2H), 1.31 (m, 2H).

Example 141-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-p-tolylurea(14)

Compound 14 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J=2 Hz, 1H), 8.18 (s, 1H), 8.13 (dd,J1=9 Hz, J2=2 Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.37 (d, J=2 Hz, 2H), 7.34(d, J=9 Hz, 1H), 7.23 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 6.13 (d,J=8 Hz, 1H), 3.60 (m, 3H), 2.95 (m, 2H), 2.20 (s, 3H), 1.87 (m, 2H),1.39 (m, 2H). MS (ESI+ ion, m/z): 560; MS (ESI− ion, m/z): 558.

Example 151-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(4-methoxyphenyl)urea(15)

Compound 15 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J=2 Hz, 1H), 8.13 (dd, J1=9 Hz, J2=2Hz, 1H), 8.10 (s, 1H), 7.55 (t, J=2 Hz, 1H), 7.37 (d, J=2 Hz, 2H), 7.34(d, J=9 Hz, 1H), 7.25 (dd, J1=7 Hz, J2=2 Hz, 2H), 6.79 (dd, J1=7 Hz,J2=2 Hz, 2H), 6.08 (d, J=8 Hz, 1H), 3.68 (s, 3H), 3.59 (m, 3H), 2.95 (m,2H), 1.87 (m, 2H), 1.38 (m, 2H). MS (ESI+ ion, m/z): 576. MS (ESI− ion,m/z): 574.

Example 161-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(furan-2-ylmethyl)urea(16)

Compound 16 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.54 (m, 2H), 7.36 (d, J=2 Hz, 2H), 7.33 (d, J=9 Hz, 1H), 6.36(m, 1H), 6.16 (m, 1H), 6.12 (m, 1H), 5.98 (d, J=8 Hz, 1H), 4.16 (d, J=6Hz, 1H), 3.54 (m, 3H), 2.91 (m, 2H), 1.81 (m, 2H), 1.31 (m, 2H). MS(ESI+ ion, m/z): 550. MS (ESI− ion, m/z): 548.

Example 171-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-isopropylthiourea(17)

Compound 17 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=2 Hz, J2=9Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.34 (m, 3H), 7.19 (m, 1H), 7.12 (m, 1H),4.22 (m, 1H), 4.10 (m, 1H), 3.61 (m, 2H), 2.90 (m, 2H), 1.93 (m, 2H),1.39 (m, 2H), 1.08 (d, J=7 Hz, 6H). MS (ESI+ ion, m/z): 529. MS (ESI−ion, m/z): 525.

Example 181-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(3-(methylthio)propyl)thiourea(18)

Compound 18 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J=2 Hz, 1H), 7.78 (dd, J1=2 Hz, J2=9Hz, 1H), 7.29 (t, J=2 Hz, 1H), 7.02 (d, J=9 Hz, 1H), 7.00 (d, J=2 Hz,2H), 6.20 (m, 1H), 5.98 (m, 1H), 4.35 (m, 1H), 3.91 (m, 2H), 3.46 (m,2H), 2.88 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.19 (m, 2H), 2.10 (s, 3H),1.87 (m, 2H), 1.57 (m, 2H). MS (ESI+ ion, m/z): 573. MS (ESI− ion, m/z):572.

Example 19N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3,5-dimethylisoxazole-4-sulfonamide(19)

Compound 19 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.24 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.34 (m, 3H), 3.54 (m, 2H), 3.16 (m, 1H),2.88 (m, 2H), 2.57 (s, 3H), 2.31 (s, 3H), 1.61 (m, 2H), 1.39 (m, 2H). MS(ESI− ion, m/z): 583.

Example 20N-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)morpholine-4-carboxamide(20)

Compound 20 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.11 (dd, J1=9 Hz, J2=2Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.36 (s, 2H), 7.31 (d, J=9 Hz, 1H), 6.30(d, J=8 Hz, 1H), 3.67 (m, 1H), 3.57 (m, 1H), 3.52 (m, 4H), 3.23 (m, 4H),2.85 (m, 2H), 1.79 (m, 2H), 1.41 (m, 2H). MS (ESI+ ion, m/z): 539.

Example 211-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-propylurea(21)

Compound 21 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.36 (s, 2H), 7.32 (d, J=9 Hz, 1H), 5.83(d, J=8 Hz, 1H), 5.71 (t, J=6 Hz, 1H), 3.57 (m, 2H), 3.50 (m, 1H), 2.91(m, 4H), 1.79 (m, 2H), 1.32 (m, 4H), 0.81 (t, J=7 Hz, 3H). MS (ESI+ ion,m/z): 511.

Example 221-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-morpholinoethyl)urea(22)

Compound 22 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.35 (s, 2H), 7.33 (d, J=9 Hz, 1H), 6.07(d, J=8 Hz, 1H), 5.62 (t, J=5 Hz, 1H), 3.56 (m, 6H), 3.51 (m, 1H), 3.08(m, 2H), 2.91 (m, 2H), 2.33 (m, 4H), 2.28 (m, 2H), 1.80 (m, 2H), 1.29(m, 2H). MS (ESI+ ion, m/z): 582.

Example 231-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-cyclohexylurea(24)

Compound 24 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 8.12 (dd, J1=9 Hz, J2=2Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.36 (d, J=2 Hz, 2H), 7.32 (d, J=9 Hz,1H), 5.74 (d, J=8 Hz, 1H), 5.60 (d, J=8 Hz, 6H), 3.54 (m, 2H), 3.49 (m,1H), 2.90 (m, 2H), 1.79 (m, 2H), 1.71 (m, 2H), 1.61 (m, 2H), 1.50 (m,1H), 1.25 (m, 4H), 1.05 (m, 4H). MS (ESI+ ion, m/z): 552.

Example 244-(3,5-dichlorophenylthio)-3-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-ylsulfonyl)benzonitrile(26)

Compound 26 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.29 (d, J=2 Hz, 1H), 7.93 (dd, J1=9 Hz, J2=2Hz, 1H), 7.84 (t, J=2 Hz, 1H), 7.71 (d, J=2 Hz, 2H), 7.14 (d, J=9 Hz,1H), 4.21 (m, 1H), 3.93 (m, 2H), 2.98 (m, 2H), 2.35 (s, 6H), 2.04 (m,2H), 1.93 (m, 2H). MS (ESI+ ion, m/z): 522.

Example 254-(3,5-dichlorophenoxy)-3-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-ylsulfonyl)benzonitrile(27)

Compound 27 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.33 (d, J=2 Hz, 1H), 8.16 (dd, J1=9 Hz, J2=2Hz, 1H), 7.55 (t, J=2 Hz, 1H), 7.40 (d, J=9 Hz, 1H), 7.35 (d, J=2 Hz,2H), 4.17 (m, 1H), 3.86 (m, 2H), 2.93 (m, 2H), 2.33 (s, 6H), 2.01 (m,2H), 1.91 (m, 2H). MS (ESI+ ion, m/z): 507.

Example 263-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-ylsulfonyl)-4-(3,5-dimethylphenoxy)benzonitrile(28)

Compound 28 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.28 (d, J=2 Hz, 1H), 8.06 (dd, J1=9 Hz, J2=2Hz, 1H), 7.06 (d, J=9 Hz, 1H), 6.97 (s, 1H), 6.84 (s, 1H), 4.18 (m, 1H),3.88 (m, 2H), 2.95 (m, 2H), 2.33 (s, 6H), 2.30 (s, 6H), 1.99 (m, 2H),1.91 (m, 2H). MS (ESI+ ion, m/z): 466.

Example 273-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-ylsulfonyl)-4-(3,5-dimethylphenylthio)benzonitrile(29)

Compound 29 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.27 (d, J=2 Hz, 1H), 7.89 (dd, J1=9 Hz, J2=2Hz, 1H), 7.24 (s, 1H), 6.94 (d, J=9 Hz, 1H), 4.22 (m, 1H), 3.97 (m, 2H),3.00 (m, 2H), 2.33 (m, 12H), 2.04 (m, 2H), 1.94 (m, 2H). MS (ESI+ ion,m/z): 482.

Example 285-cyano-2-(3,5-dichlorophenoxy)-N-(1-tosylpiperidin-4-yl)benzenesulfonamide(30)

Compound 30 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.22 (d, J=2 Hz, 1H), 7.76 (dd, J1=9 Hz, J2=2Hz, 1H), 7.57 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 7.26 (m, 1H), 6.98(m, 3H), 5.11 (d, J=8 Hz, 1H), 3.60 (m, 2H), 3.22 (m, 1H), 2.43 (s, 3H),2.36 (m, 2H), 1.84 (m, 2H), 1.67 (m, 2H). MS (ESI+ ion, m/z): 482.

Example 295-cyano-2-(3,5-dimethylphenoxy)-N-(1-tosylpiperidin-4-yl)benzenesulfonamide(31)

Compound 31 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.19 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2Hz, 1H), 7.58 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 6.95 (s, 1H), 6.89(d, J=9 Hz, 1H), 6.68 (s, 1H), 4.97 (dd, J1=8 Hz, J2=2 Hz, 1H), 3.58 (m,2H), 3.21 (m, 1H), 2.42 (s, 3H), 2.38 (m, 2H), 1.86 (m, 2H), 1.61 (m,2H). MS (ESI+ ion, m/z): 540.

Example 305-cyano-2-(3,5-dichlorophenoxy)-N-(1-(3-fluorophenylsulfonyl)piperidin-4-yl)benzenesulfonamide(32)

Compound 32 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.24 (d, J=2 Hz, 1H), 7.78 (dd, J1=9 Hz, J2=2Hz, 1H), 7.53 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 6.99 (m, 3H), 4.93(t, J=7 Hz, 1H), 3.64 (m, 2H), 3.22 (m, 1H), 2.46 (m, 2H), 1.89 (m, 2H),1.65 (m, 2H). MS (ESI+ ion, m/z): 585.

Example 31 Preparation of1-(2-chloroethyl)-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)-phenylsulfonyl)piperidin-4-yl)urea(46)

3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrilewas prepared following the procedure of Example 1. The final product wasprepared by dissolving3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile(1.00 g) in THF (30 mL) followed by the addition potassium carbonate(975 mg, 3.0 eq.), then 2-chloroethyl isocyanate (496 mg, 2.0 eq.)dropwise. After stirring for 1 hour, the starting material was consumed(confirmed by HPLC), and the mixture was filtered to remove potassiumcarbonate. The resulting filtrate was concentrated in vacuo, the solidtriturated with dichlormethane and isopropyl ether, and fitted to obtaina white powder (838 mg, 67% yield, 97% purity).

Example 32 Preparation of1-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-morpholinoethyl)urea(22)

1-(2-chloroethyl)-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)-phenylsulfonyl)piperidin-4-yl)urea(838 mg), potassium carbonate (655 mg, 3.0 eq.) and morpholine (413 mg,3.0 eq.) were dissolved in acetonitrile (25 mL) and heated to reflux.After three hours, the reaction was complete (confirmed by HPLC). Themixture was then concentrated in vacuo, the solid triturated withdichlormethane and isopropyl ether to obtain a white powder. The powderwas suspended in hot acetone, cooled in an ice bath, filtered, andwashed with water to obtain the product as a white powder (601 mg, 65%yield, 97% purity).

Example 33 Preparation of1-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-morpholinoethyl)urea(22)

1-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)-piperidin-4-yl)-3-(2-morpholinoethyl)urea(22) is prepared according to the following method as an alternative tothe method of Example 32.3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)-benzonitrile(1.002 g), prepared according to Example 1, and carbonyldiimidazole (420mg, 1.1 eq.) were combined in THF (15 mL) and stirred at roomtemperature. After 5 hours, starting material was consumed (confirmed byHPLC). 4-(2-aminoethyl)morpholine (512 mg, 2.0 eq.) was added and themixture was stirred 19 hours. Concentration in vacuo provided a whitesolid, which was resuspended in dichlormethane, partitioned with water,and the aqueous layer extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to yield a whitesolid. Trituration with isopropyl ether yielded a 96% pure productaccording to HPLC. The powder was suspended in minimal amounts of hotmethanol, stirred at 60° C. for 30 minutes, cooled in an ice bath andvacuum filtered to obtain the product as a white powder (831 mg, 60.7%yield, 98% purity).

Example 341-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-thiomorpholinoethyl)urea(47)

Compound 47 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.11 (dd, J1=7 Hz, J2=2Hz, 1H), 7.54 (t, J=1 Hz, 1H), 7.35 (d, J=2 Hz, 2H), 7.32 (d, J=9 Hz,1H), 6.34 (m, 1H), 4.11 (t, J1=J2=9 Hz, 2H), 3.58 (m, 5H), 3.48 (m, 1H),2.91 (m, 3H), 2.61 (m, 1H), 1.87 (m, 2H), 1.41 (m, 2H). MS (ESI+ ion,m/z): 599.

Example 351-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-(piperidin-1-yl)ethyl)urea(48)

Compound 48 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.56 (d, J=2 Hz, 1H), 8.11 (dd, J1=8 Hz, J2=2Hz, 1H), 7.54 (t, J=2 Hz, 1H), 7.35 (d, J=2 Hz, 2H), 7.32 (d, J=9 Hz,1H), 6.36 (m, 1H), 4.11 (t, J1=J2=9 Hz, 2H), 3.54 (m, 5H), 3.46 (m, 1H),3.04 (m, 3H), 2.89 (m, 2H), 1.87 (m, 2H), 1.39 (m, 2H). MS (ESI+ ion,m/z): 580.

Example 361-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-(piperazin-1-yl)ethyl)urea(49)

Compound 49 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.11 (dd, J1=6 Hz, J2=2Hz, 1H), 7.54 (t, J1=J2=1 Hz, 1H), 7.31 (d, J=6 Hz, 1H), 4.11 (t,J1=J2=9 Hz, 2H), 3.55 (m, 5H), 2.90 (m, 3H), 2.62 (m, 3H), 2.26 (m, 1H),1.87 (m, 2H), 1.39 (m, 2H). MS (ESI+ ion, m/z): 581.

Example 371-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-(4-fluoropiperidin-1-yl)ethyl)urea(50)

Compound 50 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.12 (dd, J1=8 Hz, J2=2Hz, 1H), 7.54 (t, J1=J2=1 Hz, 1H), 7.35 (s, 2H), 7.32 (d, J=9 Hz, 1H),6.14 (d, J=8 Hz, 1H), 5.37 (m, 2H), 3.11 (m, 2H), 2.91 (m, 3H), 2.61 (m,2H), 2.41 (m, 3H), 1.88 (m, 2H), 1.81 (m, 3H), 1.72 (m, 2H), 1.30 (m,2H). MS (ESI+ ion, m/z): 598.

Example 381-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea(51)

Compound 51 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 8.26 (d, J=2 Hz, 1H), 8.11 (dd, J1=7 Hz, J2=2Hz, 1H), 7.35 (s, 2H), 7.32 (d, J=9 Hz, 1H), 6.36 (s, 1H), 4.11 (t,J1=J2=8 Hz, 2H), 3.56 (m, 5H), 3.40 (m, 2H), 3.39 (m, 3H), 2.29 (m, 1H),1.87 (m, 2H), 1.39 (m, 2H). MS (ESI+ ion, m/z): 596.

Example 391-allyl-3-(1-(5-cyano-3,4,6-trideutero-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)urea(53)

Compound 54 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 7.54 (s, 1H), 7.35 (s, 2H), 5.96 (d, J=8 Hz,1H), 5.86 (t, J=6 Hz, 1H), 5.78 (m, 1H), 5.07 (dd, J1=8 Hz, J2=2 Hz,1H), 4.99 (dd, J1=6 Hz, J2=2 Hz, 1H), 3.60 (m, 4H), 3.51 (m, 1H), 2.91(m, 2H), 1.81 (m, 2H), 1.32 (m, 2H). MS (ESI+ ion, m/z): 534.

Example 401-(1-(5-cyano-3,4,6-trideutero-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperidin-4-yl)-3-(2-(2,2,3,3,5,5,6,6-octadeutero-morpholino)ethyl)urea(54)

Compound 53 was prepared according to the methods described herein. ¹HNMR (500 MHz, DMSO-d₆) δ: 7.35 (s, 2H), 6.08 (m, 1H), 5.63 (m, 1H), 4.14(t, J1=J2=8 Hz, 2H), 3.57 (m, 3H), 3.40 (m, 2H), 2.91 (m, 1H), 1.87 (m,2H), 1.40 (m, 2H). MS (ESI+ ion, m/z): 593.

Example 41 CCR3 Receptor Binding Assay

Cells were washed once with PBS and resuspended in a binding buffer (25mM HEPES pH 7.6, 5 mM MgCl₂, 1 mM CaCl₂, 0.5% BSA, 0.1% NaN₃). 100 mL ofcell suspension (2×10⁵ cells/well) and 0.1 nM [¹²⁵I]-labeled humaneotaxin/CCL11 (2000 Ci/mmol specific activity) were mixed in a 96-wellU-bottom polypropylene plate, and incubated for 60 min at roomtemperature for the binding reaction. The cell suspension was thentransferred to a filtration plate (#MAFB, Millipore), and washed 3 timeswith the binding buffer containing 0.5 M NaCl, scintillant added, andthe radioactivity was counted on a TopCount (Packard). For thedetermination of non-specific binding, the cell suspension and[¹²⁵I]-labeled human eotaxin/CCL11 were incubated in the presence of 500nM of unlabeled human eotaxin/CCL11. See, lino et al., “Molecularcloning and functional characterization of cynomolgus monkey (Macacafascicularis) CC chemokine receptor, CCR3,” Cytokine 2002, 19, 276-286.

The biological results are summarized in Table 1, wherein A represents avalue no greater than 50 nM, and B represents a value greater than 50 nMbut no greater than 500 nM, C represents a value greater than 500 nM butno greater than 5 μM; and D represents a value greater than 5 μM.

TABLE 1 Cmpd # K_(i) Cmpd # K_(i) 1 — 2 D 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10— 11 — 12 — 13 — 14 — 15 — 16 — 17 — 18 — 19 — 20 — 21 — 22 A 23 C 24 —25 B 26 — 27 — 28 — 29 — 30 B 31 D 32 D 33 B 34 D 35 D 36 B 37 D 38 B 39D 40 — 41 — 42 — 43 — 44 B 45 C 46 — 47 A 48 A 49 A 50 A 51 A 52 C 53 A54 A

Example 42 hERG Receptor Binding Assay

Medium throughput screening of compounds for interaction with the humanEther-a-go-go related gene (hERG) was performed by modification ofequilibrium dissociation assays using 125I-labelled peptide BeKm-1.BeKm-1, a scorpion toxin from the Central Asian scorpion Buthus eupeus,selectively blocks the hERG channel. Angelo, K., et al., 2003, PflugersArch.-Eur. J. Physiol., 447: 55-63; Chiu, P J S, et al., J. Pharmacol.Sci., 2004, 95: 311-319. Isolated membrane preparations from HEK-293cells containing transfected hERG channels (hERG K+ Channel MembraneTarget Systems™; Cat #, RBHERGM400UA) (Perkin Elmer, Boston, Mass.) weresuspended in assay buffer A at a final concentration of 1:150 v/v.Compounds for screening, and non-radiolabelled BeKm-1, as well as125I-BeKm-1 radioligand (Perkin Elmer; Cat #, NEX-412; Specific Activity2,200 Ci/mmol), were also reconstituted in Buffer A. Assay componentswere incubated in 96-well, round-bottom polypropylene plates in thefollowing ratio:

25 μl compound at appropriate concentrations

25 μl radiolabelled BeKm-1 at 0.8 nM (final concentration of 0.1 nM)

150 μl membrane preparation

The assay was incubated with shaking for 1 hr at room temperature.Subsequently, the well contents were transferred to 96-well filtrationplates (GF/C multiwell plates (MultiScreen™ HTS; Millipore, 290 ConcordRoad, Billerica, Mass. 01821 USA; Cat# MSFBN6B-XX pre-soaked in 0.3%polyethyleneimine; Acros Organics, NJ; Cat#178571000). Unboundradioactivity was removed and the membranes washed 4 times with ice-coldBuffer B, under vacuum. Plates were air-dried and bound radioactivitycounted on a Packard Top-Count NXT™ microplate scintillation andluminescence counter (Packard Instrument Co., Downers Grove, Ill.).Equilibrium dissociation was analyzed and IC50 and/or Ki values werecalculated using GraphPad Prism 4™ software (GraphPad Software, SanDiego, Calif.).

Assay Buffer A: (20 nM Hepes (MP Biomedicals, LLC; 29525 FountainParkway, Solon Ohio, 441389; Cat # 1688449) in water, pH 7.2 with 1MTris (Fisher Chemicals, Fair Lawn, N.J. 07410; Cat #, BP-1757-500); 100μM KCl (Fisher Chemicals, Cat #, BP-366-500); 0.1% BSA (Sigma Aldrich,3050 Spruce Street, St. Louis, Mo. 63103; Cat #, A3059).

Assay Buffer B: 20 mM Tris HCl, pH 7.3; 150 mM NaCl (Fisher Chemicals;Cat #, S78449).

The hERG binding assay results are summarized in Table 2, wherein Arepresents no measured activity (i.e., a value greater than 100 μM), andB represents a value greater than 10 μM but less than 100 μM and Crepresents a value less than 10 μM.

TABLE 2 Cmpd # K_(i) Cmpd # K_(i) 2 A 5 A 8 A 10 A 11 A 12 A 13 A 16 A17 A 18 A 25 A 30 A 33 A 36 B 38 A 52 A

The compounds provided herein have an improved hERG profile as comparedto known CCR3 antagonists, many of which have a Ki value in the hERGbinding assay less than 10 μM.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

1. A compound of Formula I or II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are eachindependently (a) hydrogen, halo, cyano, nitro, or guanidine; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R⁷ is (a) hydrogen, halo,cyano, nitro, oxo, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); X is O or S; Y is—C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); R⁸ is hydrogen, C₁₋₆ alkyl orC₃₋₇ cycloalkyl; or Y and R⁸ together with the N atom to which they areattached form a heteroaryl comprising at least one additional O, S, or Natom; Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c),—C(S)NR^(1b)R^(1c), —S(O)R^(1a) or —S(O)₂R^(1a); m is an integer from 0to 3; R⁹ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; m is an integerfrom 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4;and each R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; or each pair of R^(1b) and R^(1c)together with the N atom to which they are attached independently formheteroaryl or heterocyclyl, with the proviso that R^(1e) is not t-butylor benzyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heterocyclyl, and heteroaryl is optionally substituted with oneor more groups, each independently selected from (a) cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q; wherein each Qis independently selected from the group consisting of (a) deuterium;(b) cyano, halo, and nitro; (c) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (d) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.
 2. The compound ofclaim 1, wherein R¹, R², R³, R⁴, and R⁵ are each independently hydrogen,halo, or C₁₋₆ alkyl; R⁶ is cyano or nitro; R⁷ is hydrogen or C₁₋₆ alkyl;R⁸ is hydrogen or C₁₋₆ alkyl; X is O or S; m is 0, 1, or 2; n is 1 or 2;p is 1, 2, 3, or 4; and Y is —C(O)R^(1a), —C(S)R^(1a),—C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c), —C(O)OR^(1e), —S(O)R^(1a) or—S(O)₂R^(1a); wherein R^(1a) R^(1c), and R^(1e) are each independently(a) C₁₋₆ alkyl, optionally substituted with one or more halo, C₁₋₆alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl,optionally substituted with one or more halo; (c) C₃₋₇ cycloalkyl,optionally substituted with one or more halo, or one or two C₁₋₆ alkyl;(d) C₆₋₁₄ aryl, optionally substituted with one or more halo, C₁₋₆alkyl, where the alkyl is further optionally substituted with one, two,or three halo or C₁₋₆ alkoxy, where the alkoxy is further optionallysubstituted with one, two, or three halo; (e) heteroaryl, optionallysubstituted with one or two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionallysubstituted with one or more halo, C₁₋₆ alkyl, where the alkyl isfurther optionally substituted with one, two, or three halo, or C₁₋₆alkoxy, where the alkoxy is further optionally substituted with one,two, or three halo; and R^(1b) is hydrogen or methyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; with the proviso that R^(1e) is not t-butyl or benzyl. 3.The compound of claim 1, wherein R⁷ is hydrogen; m is 1; n is 1; and pis 1, 2, 3, or
 4. 4. The compound of claim 1, wherein R⁸ is hydrogen ormethyl; m is 1; n is 1; and Y is —C(O)R^(1a) or —C(S)R^(1a); whereinR^(1a) is (a) C₁₋₆ alkyl, optionally substituted with one or more halo;(b) C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionallysubstituted with one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy.
 5. Thecompound of claim 1, wherein R⁸ is hydrogen or methyl; m is 1; n is 1; Yis —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein R^(1b) is hydrogen;and R^(1c) is (a) C₁₋₆ alkyl, optionally substituted with one or morehalo or C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl or heteroaryl; (b)C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl, optionallysubstituted with one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; and R^(1b)is hydrogen or methyl; or R^(1b) and R^(1c) together with the N atom towhich they are attached form heterocyclyl.
 6. The compound of claim 1,wherein R⁸ is hydrogen or methyl; m is 1; n is 1; Y is—C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c); wherein R^(1b) is hydrogen;and R^(1c) is (a) C₁₋₆ alkyl, optionally substituted with heterocyclyl;and R^(1b) is hydrogen or methyl.
 7. The compound of claim 1, wherein R⁸is hydrogen or methyl; m is 1; n is 1; and Y is —S(O)₂R^(1a); whereinR^(1a) is (a) C₁₋₆ alkyl; (b) C₆₋₁₄ aryl, optionally substituted withone or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or (c) heteroaryl,optionally substituted with one or two C₁₋₆ alkyl.
 8. The compound ofany of claim 1, wherein m is 1; n is 1; and Y and R⁸ together with the Natom to which they are attached form a 5 membered heteroaryl, whereinthe heteroaryl comprises at least one additional O, S, or N atomoptionally substituted with one or two C₁₋₆ alkyl groups.
 9. Thecompound of claim 8, wherein Y and R⁸ together with the N atom to whichthey are attached form triazolyl, optionally substituted with one or twomethyl groups.
 10. The compound of claim 1, wherein R¹, R², R³, R⁴, andR⁵ are each independently hydrogen, halo, or C₁₋₆ alkyl; R⁶ is cyano ornitro; R⁷ is hydrogen or C₁₋₆ alkyl; R⁹ is hydrogen or C₁₋₆ alkyl; X isO or S; m is 0, 1, or 2; n is 1 or 2; p is 1, 2, 3, or 4; and Z is—C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein R^(1a), R^(1c) andR^(1e) are each independently (a) C₁₋₆ alkyl, optionally substitutedwith one or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl orheteroaryl; (b) C₂₋₆ alkenyl, optionally substituted with one or morehalo; (c) C₃₋₇ cycloalkyl, optionally substituted with one or more halo,or one or two C₁₋₆ alkyl; (d) C₆₋₁₄ aryl, optionally substituted withone or more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;(e) heteroaryl, optionally substituted with one or two C₁₋₆ alkyl; or(f) C₇₋₁₅ aralkyl optionally substituted with one or more halo, C₁₋₆alkyl, where the alkyl is further optionally substituted with one, two,or three halo, or C₁₋₆ alkoxy, where the alkoxy is further optionallysubstituted with one, two, or three halo; and R^(1b) is hydrogen ormethyl; or R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl; with the proviso that R^(1e) is not t-butylor benzyl.
 11. The compound of claim 1, wherein R⁷ is hydrogen; R⁹ ishydrogen or methyl; m is 1; n is 1; and Z is —C(O)R^(1a) or —C(S)R^(1a);wherein R^(1a) is (a) C₁₋₆ alkyl, optionally substituted with one ormore halo; (b) C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or (d) C₆₋₁₄ aryl,optionally substituted with one or more halo, C₁₋₆ alkyl or C₁₋₆ alkoxy.12. The compound of claim 1, wherein R⁷ is hydrogen; R⁹ is hydrogen ormethyl; m is 1; n is 1; Z is —C(O)NR^(1b)R^(1c) or —C(S)NR^(1b)R^(1c);wherein R^(1b) is hydrogen; and R^(1c) (a) C₁₋₆ alkyl, optionallysubstituted with one or more halo or C₁₋₆ alkoxy, C₁₋₆ alkylthio,heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl; (c) C₃₋₇ cycloalkyl; or(d) C₆₋₁₄ aryl, optionally substituted with one or more halo, C₁₋₆ alkylor C₁₋₆ alkoxy; and R^(1b) is hydrogen or methyl; or R^(1b) and R^(1c)together with the N atom to which they are attached form heterocyclyl.13. The compound of claim 1, wherein R⁷ is hydrogen; R⁹ is hydrogen ormethyl; m is 1; n is 1; and Z is —S(O)₂R^(1a); wherein R^(1a) is (a)C₁₋₆ alkyl; (b) C₆₋₁₄ aryl, optionally substituted with one or morehalo, C₁₋₆ alkyl or C₁₋₆ alkoxy; or (c) heteroaryl, optionallysubstituted with one or two C₁₋₆ alkyl.
 14. The compound of claim 1,wherein R¹ is hydrogen; R² is chloro or methyl; R³ is hydrogen; R⁴ ischloro or methyl; R⁵ is hydrogen; R⁶ is cyano; R⁷ is hydrogen; X is O orS; m is 1; and n is
 1. 15. The compound of claim 1, wherein two of R¹,R², R³, R⁴, and R⁵ are halo or C₁₋₆ alkyl, and the remaining three arehydrogen.
 16. The compound of claim 1, wherein two of R¹, R², R³, R⁴,and R⁵ are chloro or methyl, and the remaining three are hydrogen. 17.The compound of claim 1, wherein X is O.
 18. The compound of claim 1,wherein X is S.
 19. A compound selected from the group consisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, and mixtures of two or more tautomers thereofand pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.
 20. A compound of Formula Ia or IIa:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomers thereofor a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are each independently (a)hydrogen, deuterium, halo, cyano, nitro, or guanidine; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R⁷ is (a) hydrogen, halo,cyano, nitro, oxo, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); X is O or S; Y is—C(O)R^(1a), —C(S)R¹, —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); R⁸ is hydrogen, C₁₋₆ alkyl orC₃₋₇ cycloalkyl; or Y and R⁸ together with the N atom to which they areattached form a heteroaryl comprising at least one additional O, S, or Natom; Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c),—C(S)NR^(1b)R^(1c), —S(O)R^(1a) or —S(O)₂R^(1a); m is an integer from 0to 3; R⁹ is hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; R^(d) is deuterium;m is an integer from 0 to 3; n is an integer from 1 to 3; p is aninteger from 1 to 4; and q is an integer from 0 to
 3. each R^(1a),R^(1b), R^(1c), R^(1d) and R^(1e) is independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; or each pair of R^(1b) and R^(1c) together with the N atomto which they are attached independently form heteroaryl orheterocyclyl, with the proviso that R^(1e) is not t-butyl or benzyl;wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moregroups, each independently selected from (a) cyano, halo, and nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q; wherein each Qis independently selected from the group consisting of (a) deuterium;(b) cyano, halo, and nitro; (c) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (d) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.
 21. The compound ofclaim 20, wherein the compound is of formula Ia and wherein: R¹, R², R³,R⁴, and R⁵ are each independently hydrogen, deuterium, halo, or C₁₋₆alkyl; R⁶ is cyano or nitro; R⁸ is hydrogen; R^(d) is deuterium; X is Oor S; m is 0, 1, or 2; n is 1 or 2; p is 1, 2, 3, or 4; q is 3; and Y is—C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c), —C(S)NR^(1b)R^(1c),—C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); wherein R^(1a), R^(1c) andR^(1e) are each independently (a) C₁₋₆ alkyl, optionally substitutedwith one or more halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, heterocyclyl orheteroaryl; (b) C₂₋₆ alkenyl, optionally substituted with one or morehalo; (c) C₃₋₇ cycloalkyl, optionally substituted with one or more halo,or one or two C₁₋₆ alkyl; (d) C₆₋₁₄ aryl, optionally substituted withone or more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;(e) heteroaryl, optionally substituted with one or two C₁₋₆ alkyl; or(f) C₇₋₁₅ aralkyl optionally substituted with one or more halo, C₁₋₆alkyl, where the alkyl is further optionally substituted with one, two,or three halo, or C₁₋₆ alkoxy, where the alkoxy is further optionallysubstituted with one, two, or three halo; and R^(1b) is hydrogen ormethyl; or R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl.
 22. The compound of claim 20, wherein thecompound is of formula Ia and wherein: R¹, R², R³, R⁴, and R⁵ are eachindependently hydrogen, deuterium, halo, or C₁₋₆ alkyl; R⁶ is cyano; R⁸is hydrogen; R^(d) is deuterium; X is O or S; m is 1; n is 1; p is 4; qis 3; and Y is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c),—C(S)NR^(1b)R^(1c), —C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); whereinR^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and R^(1b) is hydrogen or methyl; or R^(1b) and R^(1c) together with theN atom to which they are attached form heterocyclyl.
 23. The compound ofclaim 20, wherein the compound is of formula Ia and wherein: R¹, R², R³,R⁴, and R⁵ are each independently hydrogen, halo, or C₁₋₆ alkyl; R⁶ iscyano; R⁸ is hydrogen; R^(d) is deuterium; X is O or S; m is 1; n is 1;p is 4; q is 3; and Y is —C(O)NR^(1b)R^(1c); wherein R^(1c) is (a) C₁₋₆alkyl substituted with heterocyclyl; or (b) C₂₋₆ alkenyl; and R^(1b) ishydrogen.
 24. The compound of claim 20, wherein the compound is offormula IIa and wherein: R¹, R², R³, R⁴, and R⁵ are each independentlyhydrogen, deuterium, halo, or C₁₋₆ alkyl; R⁶ is cyano or nitro; R⁷ ishydrogen or C₁₋₆ alkyl; R⁹ is hydrogen or C₁₋₆ alkyl; R^(d) isdeuterium; X is O or S; m is 0, 1, or 2; n is 1 or 2; p is 1, 2, 3, or4; and q is 3; and Z is —C(O)R^(1a), —C(S)R^(1a), —C(O)NR^(1b)R^(1c),C(S)NR^(1b)R^(1c), —C(O)OR^(1e), —S(O)R^(1a) or —S(O)₂R^(1a); whereinR^(1a), R^(1c) and R^(1e) are each independently (a) C₁₋₆ alkyl,optionally substituted with one or more halo, C₁₋₆ alkoxy, C₁₋₆alkylthio, heterocyclyl or heteroaryl; (b) C₂₋₆ alkenyl, optionallysubstituted with one or more halo; (c) C₃₋₇ cycloalkyl, optionallysubstituted with one or more halo, or one or two C₁₋₆ alkyl; (d) C₆₋₁₄aryl, optionally substituted with one or more halo, C₁₋₆ alkyl, wherethe alkyl is further optionally substituted with one, two, or three haloor C₁₋₆ alkoxy, where the alkoxy is further optionally substituted withone, two, or three halo; (e) heteroaryl, optionally substituted with oneor two C₁₋₆ alkyl; or (f) C₇₋₁₅ aralkyl optionally substituted with oneor more halo, C₁₋₆ alkyl, where the alkyl is further optionallysubstituted with one, two, or three halo, or C₁₋₆ alkoxy, where thealkoxy is further optionally substituted with one, two, or three halo;and R^(1b) is hydrogen or methyl; or R^(1b) and R^(1c) together with theN atom to which they are attached form heterocyclyl.
 25. The compound ofclaim 1, wherein the compound is a hydrochloride salt.
 26. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer, ortautomer thereof; and one or more pharmaceutically acceptable carriersor excipients.
 27. The pharmaceutical composition of claim 26, furthercomprising a second therapeutic agent.
 28. The pharmaceuticalcomposition of claim 26, wherein the composition is formulated forsingle dose administration.
 29. The pharmaceutical composition of claim28, wherein the composition is formulated as oral, parenteral, orintravenous dosage form.
 30. The pharmaceutical composition of claim 29,wherein the oral dosage form is a tablet or capsule.
 31. A method forthe treatment, prevention, or amelioration of one or more symptoms of aCCR3-mediated disorder, disease, or condition in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of the compound of claim
 1. 32. A method for the treatment,prevention, or amelioration of one or more symptoms of aneosinophil-related disorder, disease, or condition in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of the compound of claim
 1. 33. A method for the treatment,prevention, or amelioration of one or more symptoms of abasophil-related disorder, disease, or condition in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of the compound of claim
 1. 34. A method for the treatment,prevention, or amelioration of one or more symptoms of a mastcell-related disorder, disease, or condition in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of the compound of claim
 1. 35. A method for the treatment,prevention, or amelioration of one or more symptoms of an inflammatorydisease in a subject, which comprises administering to the subject atherapeutically effective amount of the compound of claim
 1. 36. Themethod of claim 31, wherein the disorder, disease, or condition isselected from the group consisting of asthma, allergic asthma, exerciseinduced asthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease, Churg-Strauss syndrome, sinusitis, basophilicleukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema,COPD (chronic obstructive pulmonary disorder), arthritis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, and cardiovasculardisorders.
 37. The method of claim 36, wherein the disorder, disease, orcondition is asthma, exercise induced asthma, allergic rhinitis, atopicdermatitis, chronic obstructive plumonary disease, or allergicconjunctivitis.
 38. The method of claim 31, wherein the compound isadministered orally, parenterally, or topically.
 39. The method of claim31, wherein the compound is administered in combination with a secondtherapeutic agent.
 40. A method for modulating CCR3 activity, comprisingcontacting a CCR3 receptor with the compound of claim 1.